Effect of antibiotic prescribing in primary care on antimicrobial resistance in individual patients: systematic review and meta-analysis
BMJ 2010; 340 doi: https://doi.org/10.1136/bmj.c2096 (Published 18 May 2010) Cite this as: BMJ 2010;340:c2096All rapid responses
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Costelloe et al. marshal the evidence, and usefully estimate a pooled
Odds Ratio for the "effect of antibiotic prescribing in primary care on
antimicrobial resistance".
Costelloe carefully refers to 'emergence' of resistance , in that
there is "a higher likelihood that resistant bacteria would be isolated
from the patient". Indeed it would be newsworthy - indeed shocking - if
this were not so. Giving antibiotics that kill susceptible germs should
be expected to result in a "higher likelihood of resistant bacteria"
amongst the surviving germs. We would expect that effect to be maximal
just after the antibiotic exposure, and to wane with time, as the selction
pressure no longer applies. All this fits with simple Darwinian thinking
on survival of the 'fittest'.
What Costelloe has not shown is that antibiotics CAUSE resistance.
Pollara over-interprets the 'emergence' word and refers to the
dangers for the individual of "misuse of antibiotics". But treated
individuals already harboured the resistant strains, before they were
given the antibiotic. Unless we accept Arason's claim that “selective
acquisition of (foreign) nonsusceptible strains” from the outer ecosystem
(from the community) is indeed made the more likely. How ?
Resistance Genes are no more or less likely to arise as a result of
antibiotics. Or are we all Lamarckians now ??
Competing interests:
None declared
Competing interests: No competing interests
I thank Costelloe et al. for their paper in BMJ and systematic
review and meta-analysis of studies where the effect of antimicrobial use
on the emergence of resistance has been assessed for individual patients
in primary care.
Since the 1990s penicillin resistance of Streptococcus pneumoniae in
Iceland has been a growing problem, and such resistance is still
increasing, much faster than in most other European countries (1). Over
35% of all pneumococci are now penicillin and macrolide non-susceptible
(2). This can probably be explained by the decades of higher antimicrobial
usage in Iceland than in the other Nordic countries.
Studies of the individual relationship between antimicrobial use and
resistance in pneumococci have produced conflicting results, reflecting
differences in the study design, setting, and measures of association used
(3). In previously published studies from Iceland, 1993(4), 1998(5) and
2003(6) the carriage rate of resistant pneumococci has usually been
calculated with the total number of children carrying pneumococci as the
denominator. In all our three cross-sectional studies, the risk of
carrying penicillin-nonsusceptible (PNSP)(penicillin MIC >/=0.1 mg/l)
was 4-5 times greater during the first 7 weeks after each antimicrobial
course for children actually carrying pneumococci (1). Antimicrobial
treatment does though not appear to increase an individual's absolute risk
of carrying PNSP after treatment in some studies. However, it may
increases a patient's relative risk of carriage of PNSP (3). In French
prospective studies, antimicrobial treatment did not increase the risk of
an individual child carrying PNSP even though the proportion of PNSP
increased (i.e., only for those carrying pneumococci) (7,8). This was
mainly explained by a significant decrease in the number of individuals
carrying penicillin-susceptible pneumococci after having received
antimicrobials and thereby relatively higher PNSP rate (relative risk)
among those still carrying pneumococci.
Because of the above-mentioned observations, I recalculated the data
from all three studies for all children, i.e., not only those carrying
pneumococci (1). The results were nevertheless identical to those that had
been obtained before i.e., higher (absolute) risk of PNSP carriage for all
children recently after antimicrobial treatment. In our first study in
1993(4), 580 children of 919 had received antimicrobials over the previous
12 months, and 191 had received treatment 2-7 weeks before sampling, of
which 27 were carrying penicillin-nonsusceptible (PNSP), as opposed to
only 17 out of 389 children who had received antimicrobials 8-52 weeks
before study entry (p<_0.0001. corresponding="corresponding" figures="figures" from="from" the="the" _1998="_1998" study="study" _5="_5" show="show" that="that" of="of" _743="_743" children="children" _372="_372" had="had" received="received" antimicrobials="antimicrobials" in="in" previous="previous" _12="_12" months="months" thereof="thereof" _11="_11" _129="_129" receiving="receiving" _2-7="_2-7" weeks="weeks" carried="carried" pnsp="pnsp" as="as" opposed="opposed" to="to" only="only" _8="_8" out="out" _243="_243" _8-52="_8-52" before="before" sampling="sampling" carrying="carrying" p="p" for="for" _2003="_2003" _6="_6" _824="_824" _357="_357" preceding="preceding" months.="months." these="these" _16="_16" _104="_104" _18="_18" _253="_253" antimicrobial="antimicrobial" treatment="treatment" _1.="_1." figure="figure" shows="shows" carriage="carriage" penicillin-susceptible="penicillin-susceptible" psp="psp" and="and" all="all" i.e.="i.e." not="not" those="those" pneumococci="pneumococci" three="three" studies="studies" by="by" number="number" last="last" relatively="relatively" speaking="speaking" strains="strains" are="are" similar="similar" two="two" after="after" treatment.="treatment." results="results" therefore="therefore" congruent="congruent" with="with" french="french" prospective="prospective" _78.="_78."/> Current antimicrobial use seems therefore to encourages the uptake of
resistant pneumococci and subsequent colonisation or “selective
acquisition of (foreign) nonsusceptible strains” from the outer ecosystem
(from the community). In addition, PNSP not previously detected by our
methods may proliferate and become abundant and detectable after
antimicrobial treatment (unmasking of dormant and/or nonsusceptible
strains present in very low numbers from the mucosa)(1).
References:
1) Arason VA. Use of Antimicrobials and Carriage of Penicillin-
Resistant Pneumococci in Children. Repeated cross-sectional studies
covering 10 years. PhD thesis University of Iceland 2006.
http://www.hirsla.lsh.is/lsh/bitstream/2336/11250/3/use_of_arason_ot_1.pdf
2) Arason VA, Sigurdsson JA. The problems of antibiotic overuse;
Acute Otitis Media among Children and Resistance Development in the
Community (editorial). Scand J Prim Health Care 2010;28:65-66.
3) Lipsitch M. Measuring and interpreting associations between
antibiotic use and penicillin resistance in Streptococcus pneumoniae. Clin
Infect Dis 2001;32(7):1044-54.
4) Arason VA, Kristinsson KG, Sigurdsson JA, Stefansdottir G, Molstad
S and Gudmundsson S. Do antimicrobials increase the carriage rate of
penicillin resistant pneumococci in children? Cross sectional prevalence
study. BMJ 1996;313(7054):387-91.
5) Arason VA, Gunnlaugsson A, Sigurdsson JA, Erlendsdottir H,
Gudmundsson S and Kristinsson KG. Clonal spread of resistant pneumococci
despite diminished antimicrobial use. Microb Drug Resist 2002a);8(3):187-
92.
6) Arason VA, Sigurdsson JA, Erlendsdottir H, Gudmundsson S and
Kristinsson KG. The role of antimicrobial use in the epidemiology of
resistant pneumococci:a 10 years follow up. Microb Drug Resist 2006;12;169
-76
7) Cohen R, Bingen E, Varon E, de La Rocque N, Brahimi N, Levy C,
Boucherat M, Langue J and Geslin P. Change in nasopharyngeal carriage of
Streptococcus pneumoniae resulting from antibiotic therapy for acute
otitis media in children. Pediatr Infect Dis J 1997;16(6):555-60.
8) Varon E, Levy C, De La Rocque F, Boucherat M, Deforche D,
Podglajen I, Navel M and Cohen R. Impact of antimicrobial therapy on
nasopharyngeal carriage of Streptococcus pneumoniae, Haemophilus
influenzae, and Branhamella catarrhalis in children with respiratory tract
infections. Clin Infect Dis 2000;31(2):477-81.
Carriage rate (95% confidence interval) of penicillin-susceptible (PSP) (green) (n=648) and penicillin-nonsusceptible pneumococci (PNSP) (red) (n=97) by all children receiving antimicrobials during the 12 months prior to study entry (n=1315) for the 1993, 1998 and 2003 studies, by the number of weeks from the last antimicrobial treatment.
Competing interests:
None declared
Competing interests: No competing interests
One common challenge that doctors, especially GPs, face is persuading
expectant patients that antibiotics are not required to guarantee
symptomatic relief from likely viral infections. Along with discussing the
risk of antibiotic side effects, until now discussions on antibiotic
resistance have remained largely focused on its impact at the population
level. Undoubtedly some patients struggle to relate how this theoretical
risk impacts on their own health. However, the excellent meta-analysis by
Costelloe et al (1) provides strong evidence for doctors to explain that
misuse of antibiotics will make the patient themselves at greater risk of
acquiring antibiotic resistance. Specifically, the analysis demonstrates
that this may impact directly on their care in the short to medium term
(i.e. the next few months), by making antibiotics less effective when they
may actually be needed. Faced with this prospect, one hopes that many
patients will reason in favour of abstaining from unnecessary courses of
antibiotics, preserving one of medicine's most potent therapeutic
interventions for times of definite need.
1. Ceire Costelloe et al., “Effect of antibiotic prescribing in
primary care on antimicrobial resistance in individual patients:
systematic review and meta-analysis,” BMJ 340, no. 18 (May 18, 2010):
c2096.
Competing interests:
None declared
Competing interests: No competing interests
The Influence of Health Systems and Setting on Antibiotic Prescribing and Resistance in Individual Patients – An area in need of further research
We would like to thank Costelloe et al.(1) for their recent paper on
effect of antibiotic prescribing in primary care on antibiotic resistance
in bacteria in individual patients. This is a fascinating and detailed
paper which highlights an important global public health issue and also
links antibiotic prescribing at individual patient level to antibiotic
resistance. We would like to point to specific areas which would need
further emphasis and analysis:
1. This article describes the effect of antibiotic prescribing in
primary care. From a health systems perspective however, the issue of
antibiotic resistance is not isolated to just primary care. Even though a
majority of antibiotics might be prescribed in primary care, antibiotic
use and resistance is a reality in secondary and tertiary care facilities
and in both inpatients and outpatients.(2) Another point to note is that
different countries might use different types of antibiotics in different
settings.(3, 4) Therefore antibiotics used in primary care might be
minimally used in tertiary care and vice versa.(4)
2. Patterns of prescribing for patients vary from country to
country.(3) We know that antibiotic use is a contributor to resistance.
(5) Therefore, it would be useful to know whether there are differences in
antibiotic use between the different populations in the various studies
included in the meta-analysis. Analyzing such differences will strengthen
the evidence that countries using less antibiotics or possibly narrow
spectrum and first line antibiotics have less levels of antibiotic
resistance. A case in point is the Strama programme in Sweden which has
shown how surveillance of antibiotic use and resistance can be used as a
tool to contain antibiotic resistance.(6)
3. This meta-analysis includes studies from countries where
antibiotics were available by prescription. It however excludes a number
of low-middle income countries where antibiotic prescriptions and over the
counter sales co-exist. A few studies from such countries have shown high
levels of bacterial resistance in individuals in settings where antibiotic
use was common. (7, 8) It is therefore imperative that further studies are
carried out in such settings whereby individuals are followed up and
resistance is measured over time. A meta-analysis of such studies can then
be done to complement the present study.
References:
1. Costelloe C, Metcalfe C, Lovering A, Mant D, Hay AD. Effect of
antibiotic prescribing in primary care on antimicrobial resistance in
individual patients: systematic review and meta-analysis. BMJ.
2010;340:c2096.
2. Iosifidis E, Antachopoulos C, Tsivitanidou M, Katragkou A, Farmaki
E, Tsiakou M, et al. Differential correlation between rates of
antimicrobial drug consumption and prevalence of antimicrobial resistance
in a tertiary care hospital in Greece. Infect Control Hosp Epidemiol. 2008
Jul;29(7):615-22.
3. Ferech M, Coenen S, Malhotra-Kumar S, Dvorakova K, Hendrickx E,
Suetens C, et al. European Surveillance of Antimicrobial Consumption
(ESAC): outpatient antibiotic use in Europe. J Antimicrob Chemother. 2006
Aug;58(2):401-7.
4. Kumari-Indira S, Chandy SJ, Jeyaseelan L, Kumar R, Suresh S.
Antimicrobial prescription patterns for common acute infections in some
rural & urban health facilities of India. Indian J Med Res. 2008
Aug;128(2):165-71.
5. Goossens H. Antibiotic consumption and link to resistance. Clin
Microbiol Infect. 2009 Apr;15 Suppl 3:12-5.
6. Mölstad S, Erntell M, Hanberger H, Melander E, Norman C, Skoog G,
Stålsby Lundborg C, Söderström A, Torell E, Cars O. Sustained reduction of
antibiotic use and low bacterial resistance. A ten year follow-up of the
Swedish STRAMA programme. Lancet Infectious Diseases 2008;8:125-32.
7. Mathai E, Chandy S, Thomas K, Antoniswamy B, Joseph I, Mathai M,
et al. Antimicrobial resistance surveillance among commensal Escherichia
coli in rural and urban areas in Southern India. Trop Med Int Health. 2008
Jan;13(1):41-5.
8. Hoa NQ, Trung NV, Larsson M, Eriksson B, Phuc HD, Chuc NT, Stålsby
Lundborg C. Decreased Streptococcus pneumoniae susceptibility to oral
antibiotics among children in rural Vietnam: a community study. BMC Infect
Dis. 2010;10:85.
Competing interests:
None declared
Competing interests: No competing interests